Massachusetts Route 3 connects to the southern terminus of US 3 in Cambridge and continues south to Cape Cod. Though it shares a number, it has never been part of US 3. Both routes, which connect end-to-end, are treated as a single 91.3-mile (146.9 km) state highway by MassDOT, with mileposts increasing continuously from Cape Cod all the way to the New Hampshire state border.

US 3 begins in the south along Memorial Drive in Cambridge, along the Charles River, at an interchange with Massachusetts Avenue (Route 2A). The road continues "south" (actually east) as Route 3 towards downtown Boston, while US 3 heads west, then north along the river towards downtown Cambridge, joining with Route 2 along the way. It runs opposite Soldiers Field Road in Allston along this stretch. Passing south of the downtown area, US 3 and Route 2 transition onto the Fresh Pond Parkway and join Route 16 in a wrong-way concurrency (heading north on US 3, one is also heading west on Route 2 and east on Route 16). Near the Alewife MBTA station, Route 2 splits off as a freeway to the west (Concord Turnpike), while US 3 / Route 16 turn onto the Alewife Brook Parkway. Shortly thereafter, US 3 splits from the Parkway (which continues as Route 16) and joins Route 2A (Massachusetts Avenue) westbound, crossing into Arlington. In the center of town, US 3 and Route 2A split from Massachusetts Avenue and overlap briefly with Route 60 (in another wrong-way concurrency) before continuing as Mystic Avenue. Route 2A splits from US 3 just to the north. US 3 continues through parts of Winchester and Woburn without any major intersections before entering Burlington and interchanging with Interstate 95 / Route 128 (Yankee Division Highway) at exit 33. US 3 joins the freeway to connect with the Northwest Expressway, while its historic surface alignment continues as Route 3A.

US 3 runs along 1.6 miles (2.6 km) of I-95 (Route 128) in a wrong-way concurrency before exiting at exit 32A onto its own freeway, the Northwest Expressway.

Originally built in the 1950s, before the cancellation of the Inner Belt, the US 3 freeway was to have extended into metro Boston before being truncated to I-95. Consequently, a partially completed cloverleaf interchange connects US 3 to I-95, and exit numbers on the US 3 freeway start at 25 and increase sequentially to 36.

US 3 is one of New Hampshire's most well-known roads, as it passes through most of the state's major cities and towns and is the only highway to extend from the Massachusetts state border in the south to the Canadian border in the north. Running for 242 miles (389 km) in New Hampshire, US 3 is by far the longest signed highway in the state.

US 3 crosses the state border into Nashua and immediately becomes concurrent with the Everett Turnpike, running on the freeway for 6.7 miles (10.8 km) along the western side of the city. US 3 leaves the Everett Turnpike at exit 7E, crosses NH 101A and turns northeast for approximately 1.5 miles (2.4 km) along a segment known as the Henri Burque Highway, before turning north onto Concord Street, which soon becomes known as the Daniel Webster Highway. (Some locals erroneously refer to the Everett Turnpike from exit 7 through the I-293 interchange as Route 3 and refer to the actual US 3 only as the Daniel Webster Highway or "Old Route 3".)

US 3 continues north through the town of Merrimack and into Bedford, where it becomes South River Road. The highway parallels I-293 until it turns east in Manchester and then crosses the Merrimack River on Queen City Avenue, just after its intersection with I-293 / NH 3A and NH 114A. US 3 and NH 3A are signed in a wrong-way concurrency for approximately 0.6 miles (0.97 km) before US 3 turns north onto Elm Street towards downtown Manchester. After approximately 2.2 miles (3.5 km), US 3 turns east onto Webster Street, then joins NH 28 to proceed in a northeasterly direction towards Hooksett, interchanging with I-93. The two routes continue as Hooksett Road, then the Daniel Webster Highway.

In Suncook, NH 28 leaves to the northeast, and US 3 proceeds northwest towards Concord on Pembroke Street, becoming Manchester Street when it enters the Concord city limits. After crossing the Merrimack River and interchanging with I-93, US 3 intersects NH 3A (South Main Street), which terminates at its parent route. US 3 traverses downtown Concord as North and South Main streets (briefly overlapping with US 202 and NH 9), then follows North State Street to Fisherville Road to Village Street in Penacook before crossing the Contoocook River into Boscawen. US 3 travels north through Boscawen, briefly overlapping with US 4. The highway parallels the Merrimack River north into Franklin, where the highway meets NH 11. US 3 joins NH 11 and turns east; NH 3A also resumes at this intersection, continuing north. US 3 and NH 11 briefly form a three-route concurrency with NH 127 in Franklin, then pass through Tilton, crossing NH 132 and passing the western end of NH 140. Continuing northeast past Winnisquam Lake, US 3 and NH 11 reach Laconia and turn onto the Laconia-Gilford Bypass, intersecting with NH 106, NH 107, and NH 11A. At the northern end of the bypass, US 3 and NH 11 split after a 17.3-mile (27.8 km) overlap, with the U.S. highway continuing north on Lake Street to Weirs Beach and an intersection with NH 11B. US 3 continues north as the Daniel Webster Highway to Meredith at the northern end of Meredith Bay on Lake Winnipesaukee. In Meredith, US 3 intersects the northern terminus of NH 106, then joins NH 25 and continues north past Squam Lake into Holderness, passing the western termini of NH 25B and NH 113. Through Holderness, US 3 and NH 25 gradually turn west, then southwest, passing the southern end of NH 175, and then reaching the northern end of NH 132 in Ashland.

Continuing north, US 3 joins with I-93 as it passes through Franconia Notch State Park, one of the more scenic drives in the White Mountains. This stretch of freeway is known as the Franconia Notch Parkway and is the only section of Interstate highway in the country with only one lane in each direction.

US 3 separates from I-93 at exit 35, shortly north of the northern park boundary in Franconia. From there, NH 141 branches northwest and US 3 heads north and east toward Twin Mountain and a junction with US 302. This portion of the road is noted for fairly frequent moose sightings, especially during sunrise and sunset when moose are particularly active.

Heading north from Twin Mountain, US 3 passes through the village of Carroll, where NH 115 branches to the northeast and US 3 bears to the northwest and the town of Whitefield. In the center of Whitefield, NH 142 branches to the northwest and NH 116 crosses, running roughly southwest to northeast. US 3 continues north to Lancaster, where it joins US 2 in the town center, and where NH 135 branches off to the west. After US 2 leaves to the west, US 3 continues north, roughly paralleling the course of the Connecticut River (which also forms the border with Vermont), through Northumberland and Groveton, where NH 110 ends. North of Groveton, US 3 continues to follow the river, through Stratford, North Stratford, and Columbia, until it reaches Colebrook, where it crosses NH 26 and meets the southern terminus of NH 145. Still following the Connecticut River north, US 3 passes through portions of Stewartstown and Clarksville. In Stewartstown, the road turns more directly east (still following the Connecticut River, which is no longer a boundary), before resuming a northeasterly direction through Pittsburg. Its last major intersection is at the northern terminus of NH 145. US 3 continues north for another 22 miles (35 km), eventually reaching the Pittsburg-Chartierville Border Crossing, where the road crosses into Chartierville, Quebec and becomes Quebec Route 257.

In total, US 3 runs along the Connecticut River and its source lakes for approximately 70 miles (110 km).

The modern Northwest Expressway was begun near Route 110 in Lowell before World War II. In the 1950s, it was extended south to Route 128 (later overlapped by I-95), and by the 1960s, it was completed north from Chelmsford to New Hampshire. By 2005, the chronically congested four-lane road, largely with antiquated ramps around Lowell, was later widened to six lanes (as it had been in Nashua, New Hampshire, a few years prior) with a breakdown lane on both the left and right sides of the road, and many interchanges were modernized in what was comically known as "The Big Wide", in reference to Massachusetts' other "Big" construction project (the Big Dig). The roadbed and bridges were built to support a fourth lane in each travel direction for future expansion.

The $365 million, 21-mile (34 km) widening project was completed in 2005 from Burlington to the New Hampshire border.

A total of at least 4 bannered routes of U.S. Route 3 have existed. The only remaining route still designated is an unsigned business loop in Laconia, New Hampshire, internally designated U.S. Route 3 Business. The route runs along NH 11A and NH 107, and is 4.2 miles (6.8 km) long.

^Milepost readings for Massachusetts reflect the combined mileage with Massachusetts Route 3; US 3 and Route 3 are treated as one continuous route by the state, mileposts continuously increase and do not reset when the designation changes in Cambridge.[5]